Mncube Khulekani, Möller Marisa, Harvey Brian H
Centre of Excellence for Pharmaceutical Sciences (PharmaCen), Division of Pharmacology, School of Pharmacy, North-West University, Potchefstroom, South Africa.
South African Medical Research Council Unit on Risk and Resilience in Mental Disorders, Department of Psychiatry and Mental Health and Neuroscience Institute, University of Cape Town, Cape Town, South Africa.
Front Psychiatry. 2021 Nov 10;12:688150. doi: 10.3389/fpsyt.2021.688150. eCollection 2021.
Treatment-resistant depression (TRD) complicates the management of major depression (MD). The underlying biology of TRD involves interplay between genetic propensity and chronic and/or early life adversity. By combining a genetic animal model of MD and post-weaning social isolation rearing (SIR), we sought to produce an animal that displays more severe depressive- and social anxiety-like manifestations resistant to standard antidepressant treatment. Flinders Sensitive Line (FSL) pups were social or isolation reared from weaning [postnatal day (PND) 21], receiving fluoxetine (FLX) from PND 63 (10 mg/kg × 14 days), and compared to Sprague Dawley (SD) controls. Depressive-, anxiety-like, and social behaviour were assessed from PND 72 in the forced swim test (FST) and social interaction test (SIT). Post-mortem cortico-hippocampal norepinephrine (NE), serotonin (5-HT), and dopamine (DA), as well as plasma interleukin 6 (IL-6), tumour necrosis factor alpha (TNF-α), corticosterone (CORT), and dopamine-beta-hydroxylase (DBH) levels were assayed. FSL rats displayed significant cortico-hippocampal monoamine disturbances, and depressive- and social anxiety-like behaviour, the latter two reversed by FLX. SIR-exposed FSL rats exhibited significant immobility in the FST and social impairment which were, respectively, worsened by or resistant to FLX. In SIR-exposed FSL rats, FLX significantly raised depleted NE and 5-HT, significantly decreased DBH and caused a large effect size increase in DA and decrease in CORT and TNF-α. Concluding, SIR-exposed FSL rats display depressive- and social anxiety-like symptoms that are resistant to, or worsened by, FLX, with reduced plasma DBH and suppressed cortico-hippocampal 5-HT, NE and DA, all variably altered by FLX. Exposure of a genetic animal model of MD to post-weaning SIR results in a more intractable depressive-like phenotype as well as changes in TRD-related biomarkers, that are resistant to traditional antidepressant treatment. Given the relative absence of validated animal models of TRD, these findings are especially promising and warrant study, especially further predictive validation.
难治性抑郁症（TRD）使重度抑郁症（MD）的治疗变得复杂。TRD的潜在生物学机制涉及遗传倾向与慢性和/或早期生活逆境之间的相互作用。通过将MD的遗传动物模型与断奶后社会隔离饲养（SIR）相结合，我们试图培育出一种对标准抗抑郁治疗有抵抗性、表现出更严重的抑郁和社交焦虑样表现的动物。弗林德斯敏感品系（FSL）幼崽从断奶后（出生后第21天）开始进行群居或隔离饲养，从出生后第63天开始接受氟西汀（FLX，10mg/kg，共14天），并与斯普拉格-道利（SD）对照品系进行比较。从出生后第72天开始，在强迫游泳试验（FST）和社交互动试验（SIT）中评估抑郁样、焦虑样和社交行为。检测死后皮质-海马去甲肾上腺素（NE）、5-羟色胺（5-HT）和多巴胺（DA）水平，以及血浆白细胞介素6（IL-6）、肿瘤坏死因子α（TNF-α）、皮质酮（CORT）和多巴胺-β-羟化酶（DBH）水平。FSL大鼠表现出明显的皮质-海马单胺紊乱以及抑郁和社交焦虑样行为，后两者可被FLX逆转。接受SIR的FSL大鼠在FST中表现出明显的不动，在社交方面存在障碍，前者被FLX加重，后者对FLX有抵抗性。在接受SIR的FSL大鼠中，FLX显著提高了耗尽的NE和5-HT水平，显著降低了DBH水平，并使DA大幅增加，CORT和TNF-α降低。总之，接受SIR的FSL大鼠表现出对FLX有抵抗性或被其加重的抑郁和社交焦虑样症状，血浆DBH降低，皮质-海马5-HT、NE和DA受到抑制，所有这些都因FLX而发生不同程度的改变。将MD的遗传动物模型暴露于断奶后SIR会导致更难治的抑郁样表型以及TRD相关生物标志物的变化，这些变化对传统抗抑郁治疗有抵抗性。鉴于相对缺乏经过验证的TRD动物模型，这些发现尤其有前景，值得研究，特别是进一步的预测性验证。
